The present invention relates to novel xcex1-hydroxy acid derivatives, their preparation and use.
Endothelin is a peptide which is composed of 21 amino acids and is synthesized and released by the vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. xe2x80x9cEndothelinxe2x80x9d or xe2x80x9cETxe2x80x9d hereinafter signifies one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a great effect on vascular tone. It is known that this vasoconstriction is caused by the binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988).
Increased or abormal [sic] release of endothelin causes a persistent contraction in peripheral, renal and cerebral blood vessels, which may lead to disorders. As reported in the literature, endothelin is involved in a number of disorders; these include hypertension, myocardial infarct, heart failure, kidney failure, pulmonary hypertension, Raynaud""s syndrome, cerebral vasospasms, atherosclerosis, stroke, benign prostate hypertrophy and asthma (Japan J. Hyperteusion [sic] 12, 79 (1989), J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990), Nature 344, 114 (1990), N. Engl. J. Med. 322, 205 (1989), N. Engl. J. Med. 328 1732 (1993), Nephton [sic] 66, 373 (1994), Stroke 25, 904 (1994), Nature 365, 759 (1993), J. Mol. Cell. Cardist. 27, A234 (1995), Cancer Research 56, 663 (1996)).
A compound having the formula A 
is mentioned in the European patent application with the file number P 44 36 851.8 (page 32, compound I-28). However, this compound cannot be prepared by the preparation process mentioned in this patent application.
Compounds of the formula B where R3 can be, for example, phenyl, and R2 and R4 can be hydrogen or C1-C4-alkyl, are described in the European patent with the number 0 347 811 B1 as substances with herbicidal activity. 
The invention relates to the xcex1-hydroxy carboxylic acid derivatives of the formula I 
where R is formyl, a tetrazole [sic], nitrile [sic], a group COOH or a radical which can be hydrolyzed to COOH. R is, for example, a group 
where R1 has the following meanings:
a) hydrogen
b) a succinylimidoxy [sic] group
c) a 5-membered heteroaromatic system, such as pyrrolyl, pyrazolyl-[sic] imidazolyl and triazolyl, which is linked via a nitrogen atom and which may carry one or two halogen atoms or one or two C1-C4-akyl or one or two C1-C4-alkoxy groups;
d) R1 furthermore a group 
where k can assume the values 0, 1 and 2, p can assume the values 1, 2, 3 and 4, and R9 is C1-C4-alkyl, C3-C7-cycloalkyl, C3-C6-alkenyl, C3-C6-alkynyl or unsubstituted or substituted phenyl which can be substituted by one or more, eg. one to three, of the following radicals: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, C1-C4-alkylthio, mercapto, amino, C1-C4-alkylamino, C1-C4-dialkylamino;
e) R1 furthermore a radical OR10, where R10 is:
hydrogen, the cation of an alkali metal such as lithium, sodium, potassium or the cation of an alkaline earth metal such as calcium, magnesium and barium, and physiologically tolerated alkylammonium ion or the ammonium ion;
C3-C8-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,
C1-C8-alkyl, in particular C1-C4-alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl;
CH2-phenyl which can be substituted by one or more of the following radicals: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, mercapto, C1-C4-alkylthio, amino, C1-C4-alkylamino, C1-C4-dialkylamino,
a C3-C6-alkenyl or C3-C6-alkynyl group, it being possible for this group in turn to carry one to five halogen atoms;
R10 can furthermore be a phenyl radical which can carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, mercapto, C1-C4-alkylthio, amino, C1-C4-alkylamino, C1-C4-dialkylamino;
a 5-membered heteroaromatic system which is linked via a nitrogen atom and contains one to three nitrogen atoms, and which may carry one or two halogen atoms and/or one or two of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, phenyl, C1-C4-haloalkoxy and/or C1-C4-alkylthio. Particular mention may be made of: 1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl, 3,5-dimethyl-1-pyrazolyl, 3-phenyl-1-pyrazolyl, 4-phenyl-1-pyrazolyl, 4-chloro-1-pyrazolyl, 4-bromo-1-pyrazolyl, 1-imidazolyl, 1-benzimidazolyl, 1,2,4-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl, 1-benzotriazolyl, 3,4-dichloroimidazol-1-yl;
f) R1 furthermore a radical 
where R11 is:
C1-C4-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C8-cycloalkyl, it being possible for these radicals to carry a C1-C4-alkoxy, C1-C4-alkylthio and/or a phenyl radical;
phenyl which is unsubstituted or substituted, in particular as mentioned above;
g) R1 a radical 
where R12 has the same meanings as R11;
h) R1 can furthermore be 
where R13 and R14 can be identical or different and have the following meanings:
hydrogen, C1-C7-alkyl, C3-C7-cycloalkyl, C3-C7-alkanyl [sic], C3-C7-alkynyl, benzyl, phenyl, unsubstituted or substituted, as described above
or R13 and R14 together form a C4-C7-alkylene chain which is closed to a ring, is unsubstituted or substituted by C1-C4-alkyl, for example, and may contain a hetero atom, eg. oxygen, nitrogen or sulfur, such as xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94(CH2)6xe2x80x94, xe2x80x94(CH2)7xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)2xe2x80x94Sxe2x80x94(CH2)2xe2x80x94, xe2x80x94CH2xe2x80x94NHxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)2xe2x80x94NHxe2x80x94(CH2)2xe2x80x94.
The other substituents have the following meanings:
W nitrogen or Cxe2x80x94NO2, furthermore W can be a CH group when one or more of the substituents R2, R3, R15 and/or R16 are a nitro group, or when X and/or Y are nitrogen;
R2 is hydrogen, halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, hydroxyl, mercapto, C1-C4-alkylthio, nitro, amino, C1-C4-alkylamino or C1-C4-dialkylamino, cyano, phenyl, optionally substituted once to three times by halogen, hydroxyl, amino, mono- or dialkyl (C1-C3)-amino, C1-C3-alkyl, C1-C3-alkoxy, mercapto or C1-C3-alkylthio, carboxyl, C1-C3-alkylcarboxyl;
or
a five- or six-membered heteroaromatic system containing one to three nitrogen atoms and/or one sulfur or oxygen atom, which carries one to three substituents as described above;
R2 can furthermore form, with the adjacent carbon atom and X, a 5- or 6-membered alkylene or alkylidene [sic] ring in each of which one or two carbon atoms can be replaced by a hetero atom such as nitrogen, sulfur or oxygen, and which can be substituted once to three times by the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, C1-C3-alkylthio, amino, C1-C3-alkylamino, C1-C3-dialkylamino;
X is nitrogen or CR15 where R15 is hydrogen, nitro, C1-C5-alkyl or C2-C5-alkenyl, optionally substituted once or twice by hydroxyl, carboxyl or phenyl, which in turn can be substituted by C1-C3-alkyl, hydroxyl or carboxyl; C1-C6-alkoxy, C1-C6-alkylthio, phenyl, hydroxyl, mercapto, nitro, amino, C1-C4-alkylamino, C1-C4-dialkylamino, cyano or carboxyl;
it is furthermore possible for CR15 to be linked to R2 to give a 5- or 6-membered ring as described above, or CR15 can form with R3 and its adjacent carbon atom a 5- or 6-membered alkylene or alkylidene [sic] ring in each of which one or two carbon atoms can be replaced by nitrogen, oxygen or sulfur, and the 5- or 6-membered ring may optionally be substituted once to three times by the following radicals:
halogen, nitro, cyano, hydroxyl, mercapto, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, C1-C3-alkylthio, amino, C1-C3-alkylamino, C1-C3-dialkylamino or carboxyl; nitrogen in the 5-membered ring may also be substituted by a formyl or acetyl group;
R3 can have the same meanings as R2, R2 and R3 can be identical or different; it is furthermore possible for R3 to form with the adjacent carbon atom and with X a 5- or 6-membered ring as described above; it is furthermore possible for R3 to form together with the adjacent carbon atom and Y a 5- or 6-membered alkylene or alkylidene [sic] ring in each of which one or two carbon atoms can be replaced by nitrogen, oxygen or sulfur; the 5- or 6-membered ring may optionally be substituted once to three times by the following radicals:
halogen, nitro, cyano, hydroxyl, mercapto, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, C1-C3-alkylthio, amino, C1-C3-alkylamino, C1-C3-dialkylamino or carboxyl; nitrogen in the 5-membered ring may also be substituted by a formyl or acetyl group;
Y is nitrogen or CR16 where R16 is hydrogen, C1-C5-alkyl, C1-C5-alkoxy, C1-C5-alkylthio, nitro, phenyl, hydroxyl, halogen, cyano, amino, C1-C4-alkylamino, C1-C4-dialkylamino, mercapto or carboxyl, or CR16 forms together with R3 and its adjacent carbon atom a 5- or 6-membered ring as described above;
R4 is phenyl, naphthyl, dihydro- or tetrahydronaphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, phenyl, C1-C4-alkylthio, amino, C1-C4-alkylamino or C1-C4-dialkylamino, it being possible for two radicals on adjacent carbon atoms to form, together with the latter, a five- or six-membered ring which is linked by an alkylene or alkylidene [sic] group and in which one or more methylene or methylidene [sic] groups can be replaced by oxygen, such as xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94 or xe2x80x94Oxe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94;
R4 can be, for example, the following radicals: 
R4 can furthermore be a five- or six-membered heteroaromatic system which contains a nitrogen, sulfur or oxygen atom and which can carry one or two of the following radicals: halogen, cyano, nitro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, phenoxy, C1-C4-alkylthio, C1-C4-alkylamino or C1-C4-dialkylamino;
in addition, R4 and R5 can be phenyl groups which are connected together in the ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO2xe2x80x94, NHxe2x80x94 or N-alkyl group;
R5 can have the same meanings as R4, it being possible for R4 and R5 to be identical or different;
R6 is hydrogen, C1-C8-alkyl, C2-C8-alkenyl or C3-C8-alkynyl, it being possible for each of these radicals to be substituted one or more times by: halogen, nitro, cyano, C1-C4-alkoxy, hydroxyl, C1-C4-alkylthio, mercapto, C1-C4-haloalkoxy, carboxyl, C1-C4-alkylcarboxyl, C1-C4-alkylcarbonyl, amino, C1-C4-alkylamino, C1-C4-dialkylamino or phenyl, or naphthyl which can in turn be substituted one or more times by: halogen, nitro, cyano, hydroxyl, C1-C4-alkoxy, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-haloalkoxy, mercapto, C1-C4-alkylthio, amino, C1-C4-alkylamino, C1-C4-dialkylamino or phenoxy, R6 is furthermore C1-C4-alkyl which is substituted by phenoxymethyl in which the phenyl group can be substituted once or twice by halogen, methyl or methoxy;
R6 is furthermore also a C1-C8-alkyl, C3-C8-alkenyl or C3-C8-alkynyl chain which is substituted by of the following radicals:
a five- or six-membered heteroaromatic system which contains one to three nitrogen atoms and/or one sulfur or oxygen atom and which can carry one to four halogen atoms and/or one or two of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals in turn to carry one to five halogen atoms and/or one to three of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and/or C1-C4-alkylthio;
or one of the following radicals: 
The compounds and the intermediates II for preparing them may have one or more asymmetrically substituted carbon atoms. Such compounds may be in the form of pure enantiomers or pure diastereomers or of a mixture thereof. It is preferred to use an enantiomerically pure compound as active substance.
The invention furthermore relates to the use of the abovementioned amino acid derivatives for producing drugs, in particular for producing inhibitors for endothelin receptors.
The compounds according to the invention are prepared by reacting a hydroxy acid derivative II in which the substituents have the stated meaning with compounds of the general formula III, 
where R17 is halogen or R18 xe2x80x94SO2xe2x80x94, where R18 can be C1-C4-alkyl, C1-C4-haloalkyl or phenyl.
The reaction preferably takes place in an inert diluent with the addition of a suitable base, ie. a base which deprotinates the intermediate II, at a temperature in the range from room temperature to the boiling point of the solvent.
Examples of such solvents or diluents are water, aliphatic, alicyclic and aromatic hydrocarbons, which may be chlorinated, such as hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachoride, ethylene chloride and trichloroethylene, ethers such as diisopropyl ether, dibutyl ether, propylene oxide, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, alcohols such as methanol, ethanol, isopropanol, butanol and ethylene glycol, esters such as ethyl acetate and amyl acetate, amides such as dimethylformamide and dimethylacetamide, sulfoxides and sulfones, such as dimethyl sulfoxide and sulfolane, and bases such as pyridine, N-methylpyrrolidone, cyclic ureas such as 1,3-dimethyl-2-imidazolidinone and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction is preferably carried out at a temperature in the range from 0xc2x0 C. to the boiling point of the solvent or mixture of solvents.
It is possible to use as base an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, eg. sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an organometallic compound such as butyllithium or an alkali metal amide such as lithium diisopropylamide or lithium amide, or tertiary amines, eg. triethylamine, pyridine, 4-N,N-dimethylaminopyridine, imidazole or diazobicycloundecane [sic].
The invention also relates to compounds of the formula II which are unknown. They can be prepared in a known manner.
For example, compounds of the formula II can be prepared by converting a nitrile of the formula IV, by alkylation with the aid of a base and of a compound R6xe2x80x94K, into a nitrile V 
as described, for example, in Ca. J. of Chem. 47 (1969) 1587 et seq., where K is a leaving group such as halogen, tosylate, mesylate or triflate.
The nitrites V are then reduced to aldehydes VI as described in Synth. Comm. 19 (1989) 355 et seq. or J. Am. Chem. Soc. 107 (1985) 4577 et seq. Reducing agents which can be used are metal hydrides such as LiAlH4 or (n-Bu)2A1H. 
The aldehydes VI are converted by known methods (as described, for example, in Chem. Pharm. Bull. 37 (1989) 2570-2) into the corresponding cyanohydrins VII: 
Cyanohydrins VII can be converted by hydrolysis, for example with aqueous HCl, or by the Pinner method with HCl gas in alcohol R10OH, into xcex1-hydroxy carboxylic acid derivatives II where 
Compounds II can also be prepared by diazotizing an amino acid derivative VIII by known methods, eg. with sodium nitrite and aqueous sulfuric acid, and hydrolyzing to the hydroxy acid derivative II as described, for example, in Synthesis (1987), 479-80. 
Amino acid derivatives VIII can be prepared, for example, in a Strecker reaction from the aldehydes VI, eg. as disclosed in Angew. Chem. Int. Ed. 26 (1987), 557 et seq. 
In addition, compounds VIII can be prepared by reacting a compound IX with a Grignard compound X, and hydrolyzing the product XI with acid to VIII, similar to the description in Liebigs Ann. (1977) 1174-1182: 
Compounds II can furthermore be synthesized by electrophilic oxidation of carboxylic acid derivatives XII, eg. with oxygen after deprotonation, as described in Tetrahedron Letters 21 (1975) 1731-4, or with Davis"" reagent 
as described in J. Org. Chem. 47 (1982) 1775-77.
Compounds XII can be prepared by reacting a suitable phosphonate compound XIII with a carbonyl compound XIV in a Wittig-Horner reaction to give the unsaturated compound XV. 
Compound XV can then be converted by a method from Chem. Ber. 64 (1931) 1493 et seq. with R5xe2x80x94H in the presence of a Friedel-Crafts catalyst such as aluminum trichloride into the carboxylic acid derivative XVI. 
Compounds I can also be prepared by reacting cyanohydrins VII with compounds III to give nitrites XVII. 
The reaction preferably takes place in an inert solvent with the addition of a suitable base as described previously.
Compounds XVII can then be converted in a known manner, for example by reaction with acids such as hydrochloric acid or sulfuric acid, with or without addition of an alcohol into compounds of type I. 
Compounds of the formula I can be obtained in enantiomerically pure form by starting from enantiomeric compounds II, which can be prepared by classical racemate resolution or by enantioselective syntheses (such as, for example, Pure Appl. Chem., 55 (1983) 1799 et seq.; Helv. Chim. Acta, 71 (1988) 224 et seq.; J. Am. Chem. Soc, 110 (1988) 1547-1557; Chem. Eng. News (1989) 25-27) in enantiomerically pure and, where appropriate, diastereomerically pure form, and reacting these compounds II with III as described above. Another possibility for obtaining enantiomerically pure compounds of the formula I is classical racemate resolution of racemic or diastereomeric compounds I with suitable enantiomerically pure bases such as brucine, strychnine, quinine, quinidine, chinchonidine [sic], chinchonine [sic], yohimbine, morphine, dehydroabietylamine, ephedrine (xe2x88x92), (+), deoxyephedrine (+), (xe2x88x92), threo-2-amino-1-(p-nitrophenyl)-1,3-propanediol (+), (xe2x88x92), threo-2-(N,N-dimethylamino)-1-(p-nitrophenyl)-1,3-propanediol (+), (xe2x88x92) threo-2-amino-1-phenyl-1,3-propanediol (+), (xe2x88x92), xcex1-methylbenzylamine (+), (xe2x88x92), xcex1-(1-naphthyl)ethylamine (+), (xe2x88x92), xcex1-(2-naphthyl)ethylamine (+), (xe2x88x92), aminomethylpinone, N,N-dimethyl-1-phenylethylamine, N-methyl-1-phenylethylamine, 4-nitrophenylethylamine, pseudoephedrine, norephedrine, norpseudoephedrine, amino acid derivatives and peptide derivatives.
Preferred compounds of the formula I, both as pure enantiomers and pure diastereomers or as mixture thereof, are those where the substituents have the following meanings:
R a carboxylic acid, a carboxylic acid salt or a group which can be hydrolyzed to a carboxylic acid, as described above.
W nitrogen or Cxe2x80x94NO2;
X nitrogen or CR15 where R15 is hydrogen, nitro, C1-C5-alkyl or C1-C5-alkenyl, optionally substituted by hydroxyl, carboxyl or phenyl, which can in turn be substituted by C1-C3-alkyl, hydroxyl or carboxyl; C1-C4-alkoxy, C1-C4-alkylthio, hydroxyl, nitro, amino, cyano or carboxyl, or CR15 forms with R2 and the adjacent carbon atom a 5- or 6-membered alkylene or alkylidene [sic] ring in which one or two carbon atoms can be replaced by a hetero atom such as nitrogen, oxygen or sulfur, and which can be substituted once or twice by a C1-C3-alkyl or C1-C3-alkoxy group; nitrogen in the 5-membered ring may additionally be substituted by a CHO or COCH3 group;
R2 hydrogen, halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-alkylthio, nitro, amino, methylamino, dimethylamino or cyano; R2 can furthermore form with the adjacent carbon atom and X a 5- or 6-membered ring as described above;
R3 hydrogen, halogen, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-alkylthio, nitro, amino, methylamino, dimethylamino or cyano; R3 can furthermore form with the adjacent carbon atom and Y a 5- or 6-membered alkylene or alkylidene [sic] ring in which one or two carbon atoms can be replaced by nitrogen, oxygen or sulfur and which can be substituted once or twice by a C1-C3-alkyl or C1-C3-alkoxy group; nitrogen in the 5-membered ring may also be substituted by a formyl or acetyl group;
Y nitrogen or CR16 where R16 is hydrogen, C1-C3-alkyl, C1-C3-alkoxy, C1-C3-alkylthio, nitro, halogen, cyano, amino, methylamino, dimethylamino or carboxyl, or if CR16 forms together with R3 and its adjacent carbon atom a 5- or 6-membered ring as described above;
R4 is phenyl or naphthyl which can be substituted by one or more of the following radicals:
halogen, hydroxyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-alkylthio or phenyl, and the aromatic system may furthermore be substituted, exclusively or in addition to the abovementioned radicals, by two radicals on adjacent carbon atoms which together represent a 1,3-dioxomethylene [sic] or 1,4-dioxoethylene [sic] group and form with the adjacent carbon atoms a 5- or 6-membered ring respectively;
in addition, R4 and R5 can be phenyl groups which are connected together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, or an oxygen or sulfur atom;
R5 can have the same meanings as R4, it being possible for R4 and R5 to be identical or different;
R6 is hydrogen, C1-C6-alkyl, C2-C6-alkenyl or C3-C6-alkynyl, it being possible for each of these radicals to be substituted once to three times by:
halogen, cyano, C1-C3-alkoxy, hydroxyl, C1-C3-alkylthio, mercapto, C1-C3-haloalkoxy, carboxyl, C1-C3-alkylcarboxyl or phenyl, or naphthyl which can likewise be substituted once to three times by the following radicals:
halogen, cyano, hydroxyl, C1-C3-alkoxy, C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-haloalkoxy, mercapto, C1-C3-alkylthio, phenyl or phenoxy, or, exclusively or in addition to the abovementioned radicals, two radicals on adjacent carbon atoms may together represent a 1,3-dioxomethylene [sic] or 1,4-dioxoethylene [sic] group, and R6 can furthermore be a phenylmethoxymethyl, -ethyl or -propyl group in which the phenyl group is substituted by methyl, methoxy or halogen.
Particularly preferred compounds of the formula I, both as pure enantiomers and pure diastereomers or as mixture thereof, are those in which the substituents have the following meanings:
R a carboxylic acid, a carboxylic acid salt or a group which can be hydrolyzed to a carboxylic acid, as described above;
W nitrogen;
X nitrogen or CR15 where R15 is hydrogen, C1-C5-alkyl or C1-C5-alkenyl, optionally substituted by hydroxyl, carboxyl or phenyl, which can in turn be substituted by C1-C3-alkyl, hydroxyl or carboxyl, C1-C3-alkoxy, C1-C3-alkylthio, hydroxyl, cyano or carboxyl, or CR15 forms with R3 and the adjacent carbon atom a 5- or 6-membered alkylene or alkylidene [sic] ring in which one carbon atom can be replaced by oxygen and which can be substituted by a methoxy or methyl group;
for example, the 5- or 6-membered alkylene and alkylidene [sic] ring may have the following structures: 
R2 hydrogen, chlorine, methyl, ethyl, trifluoromethyl, nitro, methoxy, ethoxy, methylmercapto, amino, dimethylamino, methylamino; R2 may furthermore form with the adjacent carbon atom and X a 5- or 6-membered ring as described above;
R3 hydrogen, chlorine, methyl, ethyl, trifluoromethyl, nitro, methoxy, ethoxy, methylmercapto, amino, methylamino or dimethylamino;
R3 may furthermore form with Y a 5- or 6-membered alkylene or alkylidene [sic] ring in which one or two carbon atoms may be replaced by nitrogen or oxygen, and which can be substituted by a methyl or methoxy group; examples of such alkylene or alkylidene [sic] rings are: 
Y nitrogen or CR16 where R16 is hydrogen, nitro, methyl, ethyl, chlorine or cyano, or CR16 forms with R3 and its adjacent carbon atom a 5- or 6-membered ring as described above;
R4 is phenyl which carries one or two of the following radicals: halogen, hydroxyl, methoxy, ethoxy, C1-C3-alkyl, trifluoromethyl, methylmercapto, ethylmercapto or phenyl; it is furthermore possible for two substituents to represent a dioxomethylene [sic] group, exclusively or in addition to other substituents; examples of such groups representing R4 are: 
in addition, R4 and R5 can be phenyl group [sic] which are connected together in ortho positions by a direct linkage, a methylene or ethylene group;
R5 can have the same meanings as R4, and R4 and R5 can be identical or different;
R6 is hydrogen, C1-C6-alkyl or C3-C6-alkenyl, it being possible for each of these radicals to be substituted once or twice by:
chlorine, cyano, hydroxyl, carboxyl, methoxy, ethoxy, methylmercapto, methylcarboxyl, phenylmethoxy, p-methylphenylmethoxy, p-methoxyphenylmethoxy, p-fluorophenylmethoxy, or phenyl which can be substituted once or twice by the following radicals:
chlorine, fluorine, cyano, hydroxyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, methylmercapto, phenyl or phenoxy, or, exclusively or in addition to the abovementioned radicals, two radicals on adjacent carbon atoms may represent a 1,3-dioxomethylene [sic] group.
The compounds of the present invention offer a novel potential therapy for the treatment of hypertension, pulmonary hypertension, myocardial infarct, angina pectoris, acute kidney failure, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty, benign prostate hyperplasia, kidney failure caused by ischemia and by intoxication, and hypertension, and of cancers, in particular prostate cancer and skin cancer.
The good effect of the compounds can be shown in the following experiments:
For binding studies, cloned human ETA receptor-expressing CHO cells and guinea-pig cerebellar membranes with  greater than 60% ETB relative to ETA receptors were employed.
The ETA receptor-expressing CHO cells were grown in F12 medium with 10% fetal calf serum, 1% glutamine, 100 U/ml penicillin and 0.2% streptomycin (Gibco BRL, Gaithersburg, Md., USA). After 48 h, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 min. After neutralization with F12 medium, the cells were collected by centrifugation at 300xc3x97g. For cell lysis, the pellet was briefly washed with lysis buffer (5 mM Tris-HCl, pH 7.4 with 10% glycerol) and then incubated at a concentration of 107 cells/ml of lysis buffer at 4xc2x0 C. for 30 min. The membranes were centrifuged at 20,000xc3x97g for 10 min, and the pellet was stored in liquid nitrogen.
Guinea-pig cerebella were homogenized in a Potter-Elvejhem homogenizer and obtained by differential centrifugation at 1000xc3x97g for 10 min and repeated centrifugation of the supernatant at 20,000xc3x97g for 10 min.
For the ETA and ETB receptor binding assays, the membranes were suspended in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl2, 40 xcexcg/ml bacitracin and 0.2% BSA) at a concentration of 50 xcexcg of protein per assay mixture and incubated at 25xc2x0 C. with 25 pM [125I [sic]]-ET1 (ETA receptor assay) or 25 pM [125I [sic]]-RZ3 (ETB receptor assay) in the presence and absence of test substance. The nonspecific binding was determined with 10xe2x88x927 M ET1. Filtration through GF/B glass fiber filters (Whatman, England) in a Skatron cell collector (Skatron, Lier, Norway) after 30 min separated the free and the bound radioligand, and the filters were washed with ice-cold Tris-HCl buffer, pH 7.4 with 0.2% BSA. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.
Functional in vitro assay system to search for endothelin receptor (subtype A) antagonists
This assay system is a functional, cell-based assay for endothelin receptors. Certain cell s show, when they are stimulated with endothelin 1 (ET1), an increase in the intracellular calcium concentration. This increase can be measured in intact cells which have been loaded with calcium-sensitive dyes.
1-Fibroblasts isolated from rats in which an endogenous endothelin receptor of the A subtype has been detected were loaded with the fluorescent dye Fura 2-an as follows: after trypsinization, the cells were resuspended in buffer A (120 mM NaCl, 5 mm KCl, 1.5 mM MgCl2, 1 mM CaCl2, 25 mM HEPES, 10 mM glucose, pH 7.4) to a density of 2xc3x97106/ml and incubated at 37xc2x0 C. in the dark with Fura 2-am (2 xcexcM), Pluronics [sic] F-127 (0.04%) and DMSO (0.2%) for 30 min. The cells were then washed twice with buffer A and resuspended at 2xc3x97106/ml.
The fluorescent signal with Ex/Em 380/510 from 2xc3x97105 cells per ml was continuously recorded at 30xc2x0 C. The test substances and, after incubation for 3 min, ET1 were [lacuna] to the cells, the maximum change in fluorescence was determined. The response of the cells to ET1 without previous addition of a test substance served as control and was set equal to 100%.
Male SD rats weighing 250-300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and pithed. The carotid artery and jugular vein were cathetized [sic].
In control animals, intravenous administration of 1 xcexcg/kg ET1 leads to a distinct rise in blood pressure which persists for a lengthy period.
The test compounds were injected i.v. (1 ml/kg) into the test animals 5 min before administration of ET1. To determine the ET-antagonistic properties, the rise in blood pressure in the test animals was compared with that in the control animals.
The principle of the test comprises prevention of the sudden heart death caused in mice by endothelin, probably owing to constriction of the coronary vessels, by pretreatment with endothelin receptor antagonists. Intravenous injection of 10 nmol/kg endothelin in a volume of 5 ml/kg of body weight is followed within a few minutes by the death of the animals.
The lethal endothelin-1 dose is checked on each occasion on a small group of animals. If the test substance is administered intravenously, usually the endothelin-1 injection which was lethal in the reference group takes place 5 min thereafter. With other modes of administration, the times between administrations are longer, where appropriate up to several hours.
The survival rate is recorded and doses which effectively protect 50% of the animals from endothelin-induced heart death for 24 h or longer (ED 50) are determined.
Firstly a contraction is induced with K+ in segments of rabbit aorta after an initial tension of 2 g and a relaxation time of 1 h in Krebs-Henseleit solution at 37xc2x0 C. and a pH of 7.3-7.4. After washing out, an endothelin dose-effect plot is constructed up to the maximum.
Potential endothelin antagonists are administered to other preparations of the same vessel 15 min before the start of the endothelin dose-effect plot. The effects of endothelin are calculated as a % of the K+ contraction. With effective endothelin antagonists, the endothelin dose-effect plot is shifted to the right.
The compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperotoneally [sic]) in a conventional way. Administration can also take place with vapors or sprays through the nasopharyngeal space.
The dosage depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of active substance is from about 0.5 to 50 mg/kg of body weight on oral administration and from about 0.1 to 10 mg/kg of body weight on parenteral administration.
The novel compounds can be used in conventional solid or liquid pharmaceutical forms, eg. as uncoated or (film-)coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These are produced in a conventional way. For this purpose, the active substances can be processed with conventional pharmaceutical aids such as tablet binders, bulking agents, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellant gases (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The forms obtained in this way normally contain from 0.1 to 90% by weight of active substance.
The invention further relates to the combination of compounds of the formula I with inhibitors of the renin-angiotensin system (RAS). RAS inhibitors are disclosed in, for example, EP 634 175.
The combinations according to the invention are suitable for treating disorders for which compounds of the formula I also show efficacy on their own, especially for treating hypertension and chronic heart failure.
The invention further relates to the use of a structural fragment of the formula (A) 
where Rxe2x80x94R6 have the meanings stated above for compounds of the formula I, as structural element in a pharmaceutically active compound with endothelin receptor-antagonizing action.